Antibodies directed against the insulin receptor have played a central role in investigations of the insulin receptor structure and function. Initially, these antibodies were identified in the serum of patients with autoimmune forms of extreme insulin resistance or hypoglycemia. All of the anti-insulin receptor autoantibodies in the original studies shared the ability to inhibit insulin binding. More recently, however, we have identified a patient whose serum contained anti-receptor antibodies which immunoprecipitated the insulin receptor without inhibiting insulin binding. In addition, based on the recently elucidated primary sequence of amino acids in the human insulin receptor, we have synthesized peptides corresponding to specific structural domains in the receptor. Rabbits have been immunized with these peptides in order to develop anti-receptor antibodies directed against specific sites in the receptor. The antibodies have been employed to define the functions of these structural domains. In addition, anti-receptor antibodies have been used to identify structural abnormalities in patients with insulin resistant diabetes mellitus.